Disorders of the peripheral nervous systems, including trauma and peripheral neuropathies, create a disconnection between the central nervous system and its peripheral targets (i.e.-sensory receptors and muscle). Recovery from these disorders requires both regeneration of the peripheral nerve and reinnervation of targets. In patients with peripheral nerve disorders, this recovery is rarely complete, resulting in residual weakness, sensory dysfunction, and balance problems. The long term objectives of this program are to 1) advance our understanding of the constraints to full sensory and motor recovery after peripheral nervous system injury and disease, and 2) to develop strategies for enhancing recovery in peripheral nervous system disorders though scientifically- based interventions in biological processes. To achieve these goals we have formed a team of scientists and clinician-scientists to focus experimental attention on specific cellular and systems-level mechanisms that determine the responses to, and recovery from the effects of peripheral nerve injury and disease in experimental animals. There are 5 projects within this Program. The proposal begins where the biological problem begins, with the cellular mechanisms that underlie axonal degeneration. Two projects focus on the interactions between motor neurons and muscle, and two projects address the mechanisms and behavioral consequences of the poor recovery of sensory feedback in reinnervated muscles. Project 1 examines axonal degeneration in two models of nerve injury. Project 1 examines axonal degeneration in two models of nerve injury, axotomy and exposure to neurotoxins. This project will focus on the roles of calcium and proteases in these models. Project 2 tests the dependency of sensory afferent functions, including sensory transduction and central synaptic transmission, on reconnection with sensory receptor organs in muscle. This will be done by directly examining the physiology and morphology of individual regenerated sensory afferents. Project 3 asks whether altering the conditions or reinnervation of muscle fiber changes the properties of the reinnervating motoneurons. Project 4 examines the role of muscle activity in regulating synaptic transmission. Denervation-induced changes in muscle gene expression will be manipulate to test the effects on recovery. In Project 5, the manner in which abnormalities of proprioceptive pathways result in loss of coordination will be studied during locomotion and targeted reaching.